Dopamine receptor possible mechanism for FTO, obesity association

LOS ANGELES -- More evidence that certain genetic variants can affect the brain's response to tasty food was presented here.

Two genomic variants -- in the dopamine receptor D2 (DRD2) and FTO genes -- were associated with activation of the brain's reward system in 45 individuals while looking at pictures of high-calorie foods, said Tony Goldstone, MD, PhD, an endocrinologist at Imperial College London, who led the study and presented the findings here during an oral session at the annual Obesity Week conference.

The effect, which was independent of age, gender, or adiposity, was not seen when the participants viewed pictures of low-energy foods or nonfoods.

Study participants fasted overnight and underwent blood-oxygen-level dependent (BOLD) contrast imaging with fMRI to evaluate the brain's response to pictures of food. FTO(A) carriers had a greater BOLD signal for higher energy foods and a higher food appeal rating, along with having different external eating behaviors, said Goldstone.

When both variants were included in the analysis, there was no effect on how the brain responded to pictures of food, and in fact combining them lessened the effect on the brain. Goldstone said they did not know why this was. "I'm open to the audience making suggestions for why this might be the case," he said during the session.

DRD2(A1) carriers also had greater reward responses to high-energy foods only, though they also had a greater BOLD signal in the striatum when pictures of low-energy food were shown.

"Interestingly, for the first time we also found that the activation in a part of the brain called the striatum was increased when those with the variant in FTO looked at high-calorie foods, but this depended on which variant of the other gene DRD2 they possessed," said Goldstone. "The DRD2 variant alters how the dopamine system works in the brain."

The authors also expanded their findings from the initial cohort of white patients, adding 30 participants from other ethnicities, and saw similar interactions.

The FTO genetic variant, which is associated with type 2 diabetes, has previously been shown to affect dietary intake, and body mass index, in children. And a separate study presented here found that adolescents with any of four weight-associated nucleotide polymorphisms -- of which the FTO variant was one -- responded more intensely to words associated with high-energy foods.

All participants in the initial cohort were 19 to 55 years old, with a body mass index ranging from 19.1 to 53.1. Forty-four percent were categorized as lean, 31% as overweight, and 24% as obese. None of the participants had type 2 diabetes. In the expanded cohort, there were three cases of type 2 diabetes. All of the analyses adjusted for age, gender, and percentage of body fat.

The FTO variant was first found to play a role in weight in 2007, said Goldstone, and about 40% of Europeans and other ethnic groups are thought to have it. "There are a number of potential confounds that by chance or by biology might have influenced some of the findings," said Goldstone during the session, but sleep, fasting duration, mood, or impulsivity were tested for and did not affect the findings related to either DRD2 or FTO.

Goldstone said that data related to exercise was not collected, though the participants were told to not exercise the day before, and that the work needs to be replicated.

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